Novel approaches and therapies are still needed for the treatment of protein and enzyme deficiencies, particularly strategies and therapies which overcome the challenges and limitations associated with the administration of nucleic acids and the transfection of target cells. Additional approaches which modulate or supplement the expression of a deficient protein or enzyme and thus ameliorate the underlying deficiency would be useful in the development of appropriate therapies for associated disorders.
For example, the urea cycle metabolic disorders represent protein and enzyme deficiencies for which there are no currently available cures. The urea cycle is a series of biochemical reactions which occurs in many animals that produce urea ((NH2)2CO) from ammonia (NH3) and, in mammals, takes place only in the liver. Specifically, the urea cycle consists of a series of five biochemical reactions and serves two primary functions: the elimination of nitrogen as urea and the synthesis of arginine. Defects in the urea cycle result in the accumulation of ammonia and its precursor amino acids (glutamine, glutamic acid, aspartic acid, and glycine). The resulting high levels of ammonia are neurotoxic, and the triad of hyperammonemia, encephalopathy, and respiratory alkalosis characterizes the urea cycle disorders.
Ornithine transcarbamylase (OTC) deficiency represents one such urea cycle genetic disorder. Typically, a subject with OTC deficiency has a reduced level of the enzyme OTC. In the classic severe form of OTC deficiency, within the first days of life patients present with lethargy, convulsions, coma and severe hyperammonemia that quickly lead to a deteriorating and fatal outcome absent appropriate medical intervention. If left untreated, complications from OTC deficiency may include developmental delay, mental retardation and/or death.
Treatment of OTC deficient patients primarily involves the regulation of serum ammonia and hemodialysis remains the only effective means to rapidly lower serum ammonia levels. Generally, the treatment goal of urea cycle metabolic disorders is to provide sufficient protein and arginine for growth, development, and energy while preventing the development of hyperammonemia and hyperglutaminemia. Therapeutic approaches that are currently available for the therapeutic management of urea cycle metabolic disorders such as OTC deficiency rely heavily upon dietary management. There are no currently available long-term treatments or cures for urea cycle metabolic disorders. Novel therapies that increase the level or production of an affected protein or enzyme in target cells, such as hepatocytes, or that modulate the expression of nucleic acids encoding the affected protein or enzyme could provide a treatment or even a cure for metabolic disorders, including metabolic disorders such as OTC deficiency.